Coffee attenuates fibrosis by decreasing the expression of TGF‐β and CTGF in a murine model of liver damage

This study was performed to evaluate the antifibrotic properties of coffee in a model of liver damage induced by repeated administration of thioacetamide (TAA) in male Wistar rats. In this study, cirrhosis was induced by chronic TAA administration and the effects of co‐administration of conventional caffeinated coffee or decaffeinated coffee (CC, DC, respectively) for 8 weeks were evaluated. TAA administration elevated serum alkaline phosphatase (AP), γ‐glutamyl transpeptidase (γ‐GTP) and alanine aminotransferase (ALAT), liver lipid peroxidation, collagen content, depleted liver glycogen and glutathione peroxidase (GPx) activity. Additionally increased levels of a number of proteins were detected including transforming growth factor‐beta (TGF‐β), connective tissue growth factor (CTGF) and alpha‐smooth muscle actin (α‐SMA), and matrix metalloproteinase (MMP)‐2, 9 and 13. Coffee suppressed most of the changes produced by TAA. Histopathological analysis was in agreement with biochemical and molecular findings. These results indicate that coffee attenuates experimental cirrhosis; the action mechanisms are probably associated with its antioxidant properties and mainly by its ability to block the elevation of the profibrogenic cytokine TGF‐β and its downstream effector CTGF. Various components of coffee that have been related to such a favorable effect include caffeine, coffee oils kahweol, cafestol and antioxidant substances; however, no definite evidence for the role of these components has been established. These results support earlier findings suggesting a beneficial effect of coffee on the liver. However, more basic clinical studies must be performed to confirm this hypothesis. Copyright © 2012 John Wiley & Sons, Ltd.     

Influence of genetic polymorphisms and habitual caffeine intake on the changes in blood pressure,pulse rate,and calculation speed after caffeine intake: A prospective,double blind,randomized trial in healthy volunteers

The aim of this study was to investigate the contribution of gene polymorphisms, in combination with habitual caffeine consumption, to the effect of caffeine intake on hemodynamic and psychoactive parameters. A double-blind, prospective study was conducted with 201 healthy volunteers randomly allocated 2:1 to the caffeinated group (150 mL decaffeinated coffee with additional 200 mg caffeine) or decaffeinated group (150 mL decaffeinated coffee). We measured the changes in blood pressure (BP) and calculation speed upon coffee intake, stratifying with gene polymorphisms, e.g., those in adenosine A_2A receptor (ADORA2A) and cytochrome P450 (CYP) 1A2, and daily caffeine consumption (≤90 mg/day and >90 mg/day). Overall, caffeine intake independently increased BP and calculation speed (p-values < 0.05), irrespective of the polymorphisms. In stratified analysis, a statistical significance within the caffeinated group was observed for the change in systolic BP in the stratum of CYP1A2 polymorphism with daily caffeine consumption ≤90 mg/day: change in systolic BP in the CYP1A2 rs762551 CC group (mean ± SD = 11.8 ± 5.9) was higher than that in the AA/CA group (4.1 ± 5.5). Gene polymorphisms may limitedly modify the effect of caffeine intake on hemodynamic parameters in combination with habitual caffeine consumption.     

Ascorbic Acid Reduces the Adverse Effects of Delayed Administration of Tissue Plasminogen Activator in a Rat Stroke Model

Delayed treatment of stroke with recombinant tissue plasminogen activator (r‐tPA) induces overexpression of matrix metalloproteinase 9 (MMP‐9) which leads to breakdown of the blood–brain barrier (BBB) and causes more injuries to the brain parenchyma. In this study, the effect of ascorbic acid (AA), an antioxidant agent, on the delayed administration of r‐tPA in a rat model of permanent middle cerebral artery occlusion (MCAO) was investigated. Forty male rats were randomly divided into four groups: untreated control rats (ischaemic animals), AA‐treated (500 mg/kg; 5 hr after stroke) rats, r‐tPA‐treated (5 hr after stroke 1 mg/kg) rats and rats treated with the combination of AA and r‐tPA. Middle cerebral artery occlusion was induced by occluding the right middle cerebral artery (MCA). Infarct size, BBB, brain oedema and the levels of MMP‐9 were measured at the end of study. Neurological deficits were evaluated at 24 and 48 hr after stroke. Compared to the control or r‐tPA‐treated animals, AA alone (p < 0.001) or in combination with r‐tPA (p < 0.05) significantly decreased infarct volume. Ascorbic acid alone or r‐tPA + AA significantly reduced BBB permeability (p < 0.05), levels of MMP‐9 (p < 0.05 versus control; p < 0.01 versus r‐tPA) and brain oedema (p < 0.001) when compared to either the control or the r‐tPA‐treated animals. Latency to the removal of sticky labels from the forepaw was also significantly decreased after the administration of AA + r‐tPA (p < 0.05) at 24 or 48 hr after stroke. Based on our data, acute treatment with AA may be considered as a useful candidate to reduce the side effects of delayed application of r‐tPA in stroke therapy.     

Preventive effects of Ophiocordyceps sinensis mycelium on the liver fibrosis induced by thioacetamide

Thioacetamide (TAA), usually used as a fungicide to control the decay of citrus products, itself is not toxic to the liver, but its intermediates are able to increase oxidative stress in livers and further cause fibrosis. Ophiocordyceps sinensis mycelium (OSM) which contains 10% polysaccharides and 0.25% adenosine decreased (P < 0.05) the lipid accumulation and increased (P < 0.05) antioxidative capacity in livers of thioacetamide (TAA) injected rats. Meanwhile, the increased (P < 0.05) liver sizes, serum alanine transaminase (AST) and aspartate transaminase (ALT) values in thioacetamide (TAA)‐injected rats were ameliorated (P < 0.05) by OSM supplementation. Moreover, the levels of proinflammatory cytokines, such as the tumor necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β), were also reduced (P < 0.05). The fibrosis phenomena in pathological (Masson's trichrome and H&E stainings) and immunohistochemical [α‐smooth actin (αSMA) and CD86/ED1] observations in TAA‐treated rats were reduced (P < 0.05) by OSM cotreatment. The protective effect of OSM against TAA‐induced liver inflammation/fibrosis may be via downregulations (P < 0.05) of TGF‐β pathways and NFκB which further influenced (P < 0.05) the expressions of fibrotic and inflammatory genes (i. e., αSMA, Col1α, COX2). Therefore, OSM shows preventive effects on the development of TAA‐induced hepatic fibrosis.     

Reliability of total overnight salivary caffeine assessment (TOSCA) for liver function evaluation in compensated cirrhotic patients

Background and aims Systemic caffeine clearance is considered the gold standard for phenotyping cytochrome P450 1A2 in epidemiological studies, and has been recommended for the non-invasive assessment of liver function in chronic liver disease. Our aim was to find a valid, simple and reliable alternative to this method, and therefore focused our attention on the measurement of an unique salivary caffeine concentration, without drug exposure.Methods Our evaluation included 36 healthy controls, 47 patients with compensated liver cirrhosis of viral origin, and 48 obese and diabetic patients with cryptogenetic (likely metabolic) cirrhosis. All shared the same caffeine consumption habits (regular daily use of caffeinated beverages, mainly coffee). The total overnight salivary caffeine assessment (TOSCA) was determined by using a single-point concentration of salivary caffeine, after an overnight period of abstinence.Results Daily routine caffeine intake of our population was adequate for studying the TOSCA. This single-point concentration correlated well with caffeine clearance, measured by salivary concentrations of caffeine. Mean TOSCA in cirrhotic patients was significantly higher than in controls (p<0.001; sensitivity (%) 84.2 and specificity (%) 97.2; negative likelihood ratio=0.16 and positive likelihood ratio=30.32). A cut-off set at 4.2 μg/ml (sensitivity (%) 95.8 and specificity (%) 68.1; negative likelihood ratio=0.06 and positive likelihood ratio=3.0) successfully differentiated the type of cirrhosis. Rapid (with higher metabolism of caffeine) metabolizers were more frequent in the group of patients with cirrhosis of metabolic origin (70.8%; p<0.0001), and the opposite was true for the group of patients with cirrhosis of viral origin, which comprised many poor metabolizers (85.1%; p<0.001). Serum transforming growth factor-beta 1 concentration, mirroring ongoing fibrosis, ranked high in poor metabolizers. The association between overnight assessment and homeostasis model assessment in rapid metabolizers could result from similar roles for cytochrome P450 1A2 and insulin resistance in determining metabolic liver cirrhosis.Conclusion The TOSCA, although differential between the viral and metabolic etiologies, could be considered a good diagnostic use to verify the presence and eventually the type of compensated liver cirrhosis     

Caffeine is protective in patients with non-alcoholic fatty liver disease

Aliment Pharmacol Ther 2012; 35: 76–82

Summary

Background Non‐alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is the most common cause of primary liver disease. Although recent studies have found that coffee drinking is protective against end stage chronic liver disease, there are scarce caffeine intake data in NAFLD specifically. Aim To investigate the effects of dietary behaviour in NAFLD patients, using four continuous cycles of the National Health and Nutrition Examination Surveys (NHANES 2001–2008). Methods Using data from four continuous cycles of NHANES, dietary intake questionnaires that list 62 nutrition components. Logistic regression was used to identify independent predictors of NAFLD among nutrition components after adjustment for potential clinical confounders. All analyses were run using sas 9.1 and sudaan 10.0 (SAS Institute Inc., Cary, NC, USA). Results Of the 62 nutrient components used for the univariate analysis, 38% were significant (P‐value <0.05) in NAFLD with caffeine consumption being higher in the control group (P‐value <0.001). The multivariate analysis using demographics, clinical parameters and nutritional components found five factors independently associated with NAFLD [African American Race P‐value <0.001); Male gender P‐value <0.001); Obesity (BMI ≥ 30) P‐value <0.001); Caffeine intake (mg) P‐value <0.001) and total plain water consumption (g) P‐value ≤0.02)]. Conclusions Our analysis shows that caffeine intake is independently associated with a lower risk for NAFLD suggesting a potential protective effect. These data necessitate further research to elucidate the mechanism by which caffeine can protect against NAFLD.     

A naturalistic investigation of the effects of day-long consumption of tea, coffee and water on alertness, sleep onset and sleep quality

Rationale: The effects of caffeine, especially caffeinated coffee, on human performance have been extensively studied. However, few studies have been naturalistic representations of how tea/coffee is normally consumed in terms of dose and time of consumption. Objectives: This study investigated the effects of day-long consumption of tea, coffee and water on cognitive and psychomotor performance, and sleep quality at night. Methods: Thirty healthy volunteers received equal volume drinks equivalent to either 1 or 2 cups of tea (containing 37.5 mg or 75 mg caffeine), or coffee (75 mg or 150 mg caffeine), or water, in a randomised five-way crossover design. Drinks were administered on four occasions during the day (0900, 1300, 1700 and 2300 hours). A psychometric battery consisting of critical flicker fusion (CFF), choice reaction time (CRT) and subjective sedation (LARS) tests, was administered pre-dose and at frequent time points post-dose. The Leeds Sleep Evaluation Questionnaire (LSEQ) was completed each morning and a wrist actigraph was worn for the duration of the study. Results: Caffeinated beverages maintained CFF threshold over the whole day (P<0.05), independent of caffeine dose or beverage type. During the acute phase of beverage ingestion, caffeine significantly sustained performance compared to water after the first beverage for CFF and subjective sedation (P<0.05), and after the second beverage for the Recognition component of the CRT task (P<0.05). Additionally, there were significant differences between tea and coffee at 75 mg caffeine after the first drink. Compared to coffee, tea produced a significant increase in CFF threshold between 30 and 90 min post-consumption (P<0.01). However, following the second beverage caffeinated coffee at 75 mg significantly improved reaction time (P<0.05), compared to tea at the same dose, for the Recognition component of the CRT task. Caffeinated beverages had a dose dependent negative effect on sleep onset (P<0.001), sleep time (P<0.001) and sleep quality (P<0.001). Conclusions: These results indicate that ingestion of caffeinated beverages may maintain aspects of cognitive and psychomotor performance throughout the day and evening when caffeinated beverages are administered repeatedly. This study also demonstrates that day-long tea consumption produces similar alerting effects to coffee, despite lower caffeine levels, but is less likely to disrupt sleep. Other differences between tea and coffee were more subtle, and require further investigation. Received: 16 February 1999 / Final version: 20 December 1999     

Coffee drinking and cigarette smoking: II. coffee, urinary pH and cigarette smoking behavior

Two experiments designed to assess the relationship between coffee intake and smoking are reported. In Experiment I, coffee drinking smokers were randomly assigned to four groups in which they received 0, 1, 2, or 3 cups of coffee during two one-hour sessions while they worked on crossword puzzles. Results showed that subjects receiving coffee in any amount smoked more than subjects who were not provided coffee. Moderate and low rate smokers were then randomly assigned to one of five groups in Experiment II, in which they were provided no drink, water, Postum^® (a coffee substitute), caffeinated, or decaffeinated coffee. These groups were selected to assess the characteristics of coffee that may have influenced increased smoking. Results for number of cigarettes smoked and puff rate generally showed that subjects receiving caffeinated or decaffeinated coffee smoked more than subjects in the no drink or water control groups. The results of this study provide experimental evidence of the role of coffee in setting the occasion for smoking, as well as ruling out the presence of a liquid or caffeine as the important characteristics of coffee in influencing smoking.     

Does caffeine intake enhance absolute levels of cognitive performance?

The relationship between habitual coffee and tea consumption and cognitive performance was examined using data from a cross-sectional survey of a representative sample of 9003 British adults (the Health and Lifestyle Survey). Subjects completed tests of simple reaction time, choice reaction time, incidental verbal memory, and visuo-spatial reasoning, in addition to providing self-reports of usual coffee and tea intake. After controlling extensively for potential confounding variables, a dose-response trend to improved performance with higher levels of coffee consumption was observed for all four tests (P<0.001 in each case). Similar but weaker associations were found for tea consumption, which were significant for simple reaction time (P=0.02) and visuo-spatial reasoning (P=0.013). Estimated overall caffeine consumption showed a dose-response relationship to improved cognitive performance (P<0.001 for each cognitive test, after controlling for confounders). Older people appeared to be more susceptible to the performance-improving effects of caffeine than were younger. The results suggest that tolerance to the performance-enhancing effects of caffeine, if it occurs at all, is incomplete.     

Effect of decaffeination of coffee or tea on gastro-oesophageal reflux

Background: Coffee and tea are believed to cause gastrooesophageal reflux : however, the effects of these beverages and of their major component, caffeine, have not been quantified. The aim of this study was to evaluate gastro-oesophageal reflux induced by coffee and tea before and after a decaffeination process, and to compare it with water and water-containing caffeine. Methods: Three-hour ambulatory pH-metry was performed on 16 healthy volunteers, who received 300 ml of (i) regular coffee, decaffeinated coffee or tap water (n = 16), (ii) normal tea, decaffeinated tea, tap water, or coffee adapted to normal tea in caffeine concentration (n= 6), and (iii) caffeine-free and caffeine-containing water (n= 8) together with a standardized breakfast. Results: Regular coffee induced a significant (P < 0.05) gastro-oesophageal reflux compared with tap water and normal tea, which were not different from each other. Decaffeination of coffee significantly (P < 0.05) diminished gastro-oesophageal reflux, whereas decaffeination of tea or addition of caffeine to water had no effect. Coffee adapted to normal tea in caffeine concentration significantly (P < 0.05) increased gastro-oesophageal reflux. Conclusions: Coffee, in contrast to tea, increases gastrooesophageal reflux, an effect that is less pronounced after decaffeination. Caffeine does not seem to be responsible for gastro-oesophageal reflux which must be attributed to other components of coffee.     

Anabolic Effect of Insulin Therapy on the Bone: Osteoprotegerin and Osteocalcin Up‐Regulation in Streptozotocin‐Induced Diabetic Rats

Type 1 diabetes mellitus (T1DM) is associated with several skeletal alterations, particularly in conditions of poor glycaemic control. Insulin therapy is the major conservative treatment for T1DM; however, the effects of this hormone on bone markers of T1DM rats are limited, and the regulatory mechanisms remain elusive. Therefore, the evaluation of molecular and non‐molecular parameters in a chronic animal model of T1DM‐induced bone loss, treated with and without insulin, may help in elucidating the insulin mechanisms. Male Wistar rats were assigned into three groups: control, T1DM (T1DM rats induced with streptozotocin [STZ] at 40 mg/kg intravenously) and T1DM plus insulin therapy (T1DMI). After 8 weeks, we evaluated the serum biochemical, tibia histomorphometric and biomechanical parameters, as well as the gene expression of the receptor activator of nuclear factor kappa‐B ligand (RANKL), osteoprotegerin (OPG) and osteocalcin (OC) of femur mRNA. Compared with T1DM, the T1DMI group showed less bone loss, which was revealed by the increased trabecular width (TbWi, p < 0.001) and trabecular bone area (BAr, p < 0.01), reduced trabecular separation (TbSp, p < 0.01) and increased Young's modulus (p < 0.05). Moreover, molecular analyses indicated that the expression of OPG and OC was up‐regulated (p < 0.001 and p < 0.05, respectively). In summary, the up‐regulation of OPG and OC in the T1DMI group supports an anabolic effect of insulin, which was demonstrated by the maintenance of bone architecture and flexibility. These results suggest that insulin therapy may prevent T1DM‐induced bone loss via the effects on the bone formation.     

Sex Difference in Formation of Propofol Metabolites: A Replication Study

Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men – an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I‐II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose‐ and weight‐adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4‐hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4‐hydroxypropofol‐1‐O‐β‐D‐glucuronide (Q1G) and 4‐hydroxypropofol‐4‐O‐β‐D‐glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p = 0.03), Q1G (2.9 times, p < 0.001), Q4G (2.4 times, p < 0.01) and OHP (4.6 times, p = 0.01) were found in women (n = 53) than in men (n = 45) after intravenous infusion of propofol using target‐controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women – a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.     

Effects of coffee on driving performance during prolonged simulated highway driving

Rationale

Coffee is often consumed to counteract driver sleepiness. There is limited information on the effects of a single low dose of coffee on prolonged highway driving in non-sleep deprived individuals.

Objectives

The aim of this study was to examine the effects of a single cup of coffee (80?mg caffeine) on simulated highway driving performance.

Methods

Non-sleep deprived healthy volunteers (n?=?24) participated in a double-blind, placebo-controlled, crossover study. After 2?h of monotonous highway driving, subjects received caffeinated or decaffeinated coffee during a 15-min break before continuing driving for another 2?h. The primary outcome measure was the standard deviation of lateral position (SDLP), reflecting the weaving of the car. Secondary outcome measures were speed variability, subjective sleepiness, and subjective driving performance.

Results

The results showed that caffeinated coffee significantly reduced SDLP as compared to decaffeinated coffee, both in the first (p?=?0.024) and second hour (p?=?0.019) after the break. Similarly, the standard deviation of speed (p?=?0.024; p?=?0.001), mental effort (p?=?0.003; p?=?0.023), and subjective sleepiness (p?=?0.001; p?=?0.002) were reduced in both the first and second hour after consuming caffeinated coffee. Subjective driving quality was significantly improved in the first hour after consuming caffeinated coffee (p?=?0.004).

Conclusions

These findings demonstrate a positive effect of one cup of caffeinated coffee on driving performance and subjective sleepiness during monotonous simulated highway driving.     

Coffee drinking and cigarette smoking: I. coffee,caffeine and cigarette smoking behavior

Two experiments designed to assess the relationship between coffee intake and smoking are reported. In Experiment I, coffee drinking smokers were randomly assigned to four groups in which they received 0, 1, 2, or 3 cups of coffee during two one-hour sessions while they worked on crossword puzzles. Results showed that subjects receiving coffee in any amount smoked more than subjects who were not provided coffee. Moderate and low rate smokers were then randomly assigned to one of five groups in Experiment II, in which they were provided no drink, water, Postum^® (a coffee substitute), caffeinated, or decaffeinated coffee. These groups were selected to assess the characteristics of coffee that may have influenced increased smoking. Results for number of cigarettes smoked and puff rate generally showed that subjects receiving caffeinated or decaffeinated coffee smoked more than subjects in the no drink or water control groups. The results of this study provide experimental evidence of the role of coffee in setting the occasion for smoking, as well as ruling out the presence of a liquid or caffeine as the important characteristics of coffee in influencing smoking.     

Toxic effects of methamidophos on paraoxonase 1 activity and on rat kidney and liver and ameliorating effects of alpha‐tocopherol

The role of alpha‐tocopherol on nephrotoxicity and hepatotoxicity induced by methamidophos (MT) was investigated in wistar rats. Animals were given via gavage, for four weeks, a low dose of MT (MT1), a high dose of MT (MT2), vitamin E (200 mg/kg of bw) or both MT2 plus vitamin E (Vit E) and control group was given distillate water. MT treatment resulted in a significant decrease in the body weight of MT2‐treated group. Moreover, MT‐treated groups had significantly lower butyrylcholinesterase (p < 0.01) and paraoxonase 1 (PON1) activities compared with the control group (p < 0.05). However, MT2‐treated group had significantly higher alkaline phosphatase activity compared with untreated rats (p < 0.05). Both MT‐treated groups had significantly higher urea (p < 0.01) and uric acid levels (p < 0.05) compared with the control group. However, significant low uric acid level (p < 0.05) was noted in MT2 plus vit E‐treated rats compared with MT2‐treated group. Histopathological changes in organ tissues were observed in both MT‐treated groups and MT2 plus vit E‐treated rats. However, the damage was reduced in MT2 plus vit E‐treated rats. Therefore, this study deduces that alpha‐tocopherol administration may ameliorate the adverse effects of subacute exposure to MT on rat liver and kidney and this antioxidant can protect PON1 from oxidative stress induced by this organophosphorus pesticide. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 842–854, 2016.     

Zolpidem 10 mg given at daytime is not antagonized by 300 mg caffeine in man

Objective: Caffeine counteracts various effects of traditional benzodiazepines (BZDs). As zolpidem, a short-acting hypnotic, is an atypical GABA_A-BZD agonist, we investigated when caffeine would counteract the effects of zolpidem as well. Methods: In daytime study I, zolpidem 10 mg (capsule) and caffeine 150 or 300 mg (in decaffeinated coffee) were given, alone and in combinations, to parallel groups (n= 15–17) of healthy students in double-blind and placebo-controlled manner. Objective and subjective tests were done before and 45 min and 90 min after intake. Ranked Δ values (changes from baseline) were analysed by one-way contrast ANOVA and Scheffe's tests. In daytime study II, four healthy subjects took zolpidem 10 mg alone, and together with blinded caffeine 250 mg or (at −45 min) erythromycin 750 mg. Objective and subjective effects were measured and plasma zolpidem concentrations assayed at baseline and 45 min and 90 min after zolpidem intake. Results: In study I, practice effects after placebo (ad + 30%) were seen for letter cancellation and digit symbol substitution but not for flicker fusion tests. Zolpidem alone significantly impaired (P < 0.05 vs Δ-placebo) letter cancellation and digit symbol substitution at 45 min and 90 min, lowered the flicker fusion threshold at 45 min, and caused subjective drowsiness, mental slowness, clumsiness and feeling of poor performance. Caffeine alone showed a non-significant trend to improve objective performance. The combined effects of zolpidem and either dose of caffeine matched those measured after zolpidem alone. Zolpidem + caffeine 300 mg was not stronger than zolpidem + caffeine 150 mg in impairing immediate memory and causing subjective sedation. In study II, zolpidem caused objective and subjective sedation; neither caffeine nor erythromycin modulated the effects of zolpidem or plasma zolpidem concentrations. Conclusion: The sedative effects of 10 mg of zolpidem are not antagonized by 150–300 mg of caffeine in pharmacodynamic or pharmacokinetic terms. Received: 15 December 1997 / Accepted in revised form: 11 March 1998     

Protective effects of coffee‐derived compounds on lipopolysaccharide/d‐galactosamine induced acute liver injury in rats

Objectives The protective effects of coffee‐derived compounds on lipopolysaccharide/d‐galactosamine (LPS/d‐GalN) induced acute liver injury in rats were investigated. Methods Wistar rats were orally administered saline (control) or one of the test compounds (caffeine, chlorogenic acid, trigonelline, nicotinic acid or eight ***pyrazinoic acids) at a dose of 100 mg/kg, respectively. This was followed by intraperitoneal injection with LPS (100 μg/kg)/d‐GalN (250 mg/kg) 1 h after administration of the test compounds. Blood samples were collected up to 12 h after LPS/d‐GalN injection, followed by determination of plasma aspartate aminotransferase, alanine aminotransferase, tumour necrosis factor α (TNF‐α) and interleukin 10 (IL‐10) levels. Key findings Plasma aspartate aminotransferase and alanine aminotransferase levels were significantly increased after LPS/d‐GalN‐treatment, but were suppressed by pretreatment with caffeine (n = 5), nicotinic acid, non‐substituted pyrazinoic acid or 5‐methylpyrazinoic acid (n = 6, respectively) 12 h after LPS/d‐GalN‐treatment (P < 0.01, respectively). Moreover, the animals pretreated with these test compounds showed significantly higher survival rates (83–100%) compared with the control (23%). Only pretreatment with caffeine significantly suppressed the LPS/d‐GalN induced elevation of plasma TNF‐α levels 1 and 2 h after LPS/d‐GalN‐treatment (P < 0.01, respectively). Pretreatment with caffeine, nicotinic acid or non‐substituted pyrazinoic acid activated the LPS/d‐GalN induced elevation of plasma IL‐10 levels at 1 and 2 h, although there were no statistically significant differences in IL‐10 levels between control and nicotinic acid or non‐substituted pyrazinoic acid treated rats. Conclusions The results suggest that caffeine, nicotinic acid, non‐substituted pyrazinoic acid and 5‐methylpyrazinoic acid can protect against LPS/d‐GalN induced acute liver injury, which may be mediated by the reduction of TNF‐α production and/or increasing IL‐10 production.     

Behavioral effects of nicotine, amphetamine and cocaine under a fixed-interval schedule of food reinforcement in rats chronically exposed to caffeine

 Epidemiological surveys demonstrate that caffeine, the main psychoactive ingredient of coffee, is a positive correlate in drug abuse. To characterize the behavioral nature of caffeine interactions with other psychomotor stimulants, we examined the effects of chronic caffeine exposure on the behavioral responses to nicotine, amphetamine, cocaine, the selective D₁ agonist SKF-82958 and the selective D₂ receptor agonist NPA, in rats responding under a fixed interval (FI) schedule of food reinforcement. Following stabilization of rates and temporal patterns of responding (mathematically expressed as quarter-life values, QL), twenty-one Sprague-Dawley rats responding under a 5-min FI schedule of food reinforcement were divided into two groups; one (twelve rats) maintained on tap water (control) and the other (nine rats) on caffeine (3 mg/ml added to the drinking water). Following the substitution of caffeine solution for tap water, behavior was temporarily disrupted as evidenced by decreases in responding and QL values which reached a maximum after 72 h (rate 60% and QL 30% below baseline levels). Rats developed complete tolerance to these effects of caffeine over 5 days of caffeine exposure. After response rate and QL values stabilized, effects of drugs were evaluated. Nicotine (0.01–1.0 mg/kg; SC), amphetamine (0.1–5.6; IP), and cocaine (1.0–17; IP) each produced biphasic dose-dependent changes in response rate with maximum increases in response rate following intermediate doses and decreases in response rates following higher doses. The increase in rates of responding produced by amphetamine or cocaine (but not nicotine) were greater (P<0.05) in caffeine-drinking than in water-drinking rats. Both SKF-82958 (0.001–0.3 mg/kg; IP) and NPA (0.0001–0.1; IP) produced only dose-dependent decreases in rates of responding. Caffeine-drinking rats were less sensitive to the rate-depressant effects of SKF-82958 (P<0.05) than water-drinking rats. However, similar changes (P>0.05) were produced by NPA in both groups. Except for amphetamine, the remaining drugs produced similar (P>0.05) dose-dependent decreases in QL values in water- and caffeine-drinking rats. Amphetamine produced smaller decreases in QL values in caffeine-drinking rats than in water-drinking rats (P<0.05). Chronic exposure to caffeine produced complete insurmountable tolerance to the response-rate increasing (stimulant) effects of acute caffeine (3.0–17 mg/kg; IP) in caffeine-drinking rats. In conclusion, our study revealed that chronic caffeine exposure potentiates the behavioral response to amphetamine and cocaine but not to that of nicotine in rats responding under a FI schedule of food reinforcement. Thus, it is likely that these effects are mediated through different pharmacological mechanisms. Received: 3 September 1997 / Final version: 9 May 1998